Abstract 1096: Co-targeting of AKT and Pim kinases in mousePTEN-deficient prostate cancer

AKT and Pim kinases modulate programmed cell death by the phosphorylation of common substrates that regulate apoptosis and other survival processes. Evidence suggests that the antitumor effects of targeted Akt inhibition can be inhibited or diminished by the JAK/STAT-dependent induction of Pim kinases. In this study we examined the therapeutic potential of co-targeting AKT and Pim in a genetically engineered mouse model of prostate cancer driven by the conditional inactivation of PTEN. The antitumor effects of AZD5363, a pan AKT inhibitor, and AZD1208, a highly potent Pim kinase inhibitor, were investigated as monotherapy or in combination on mice harboring castration-naive prostate tumors and mice that developed castration-resistant disease. Mice were randomized treated for four weeks. Safety and tolerability was assessed by bodyweight changes. Antitumor activity was determined by differences in tumor burden, proliferation and apoptosis and histology. Molecular activity was assessed by examining the phosphorylation of common substrates by western blot analysis. Treatments were well-tolerated and no significant differences in bodyweight changes were observed. In castration-naive prostate tumors, treatments with AZD5363, AZD1208 and AZD5363/AZD1208 resulted in 11.9%, 13.5% and 36.9% reductions of tumor burden compared to vehicle treated controls, respectively, P Citation Format: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Naomi Ando, Noriko Sato, Kazuko Sakai, Barry R. Davies, Dennis Huszar, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Co-targeting of AKT and Pim kinases in mouse PTEN-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1096. doi:10.1158/1538-7445.AM2017-1096